Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia. Interactions of this pathogen with humans are complex, with pneumococcus causing a spectrum of disease ranging from asymptomatic colonization of upper airways to multi-organ infection and death. We propose to elucidate the hepatic acute phase response triggered by pneumococci in the lungs, and to examine whether pneumococcal subversion of this response is a critical virulence determinant during lung infection. The hepatic acute phase response is triggered by cytokines during pneumonia, with liver activation dependent on IL-6 (triggering STAT3) and on TNF and IL-1 (triggering NF-?B). We postulate that expression of these cytokines during pneumonia is driven by NF-?B RelA in resident lung myeloid cells, and these cytokines then activate both STAT3 and NF-?B in hepatocytes to mediate acute phase protein expression essential to preventing the spread of infection and inflammatory injury from the lungs to other organs and tissues. To test the central hypothesis that the hepatic acute phase response functions as a vascular shield to prevent dissemination of infection and injury from the infected lung, we propose to pursue the following specific aims: 1) Test the hypothesis that lung resident macrophages and dendritic cells initiate the hepatic acute phase response during pneumonia, using mice in which cytokine expression is inhibited by RelA mutation selectively in myeloid cells and in resident lung leukocytes. 2) Test the hypothesis that the hepatic acute phase response limits both dissemination of infection (bacteremia) and dissemination of injury (ARDS and multi-organ failure) during pneumonia, using mice in which the hepatic acute phase response is inhibited by combined targeting of both STAT3 and RelA selectively in hepatocytes. 3) Test the hypothesis that pneumococci subverting the hepatic acute phase response are more invasive in human patients and mouse models, using clinical isolates from human patients with asymptomatic carriage or bacteremic pneumonia in in vitro screens and in vivo models of infection. Innovations include the novel concepts to be tested, as well as the mice deficient in RelA and/or STAT3 in select cells and the in vitro screening assays of clinical isolates of pneumococcus. The proposed studies will have significance for filling knowledge gaps (elucidating the regulation and function of the acute phase response during pneumonia) and will guide further studies aiming to differentiate and treat particularly susceptible patients and especially virulent pneumococci. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae (pneumococcus) infection is the leading cause of pneumonia, and the spreading of pneumococcus from the lungs also causes bloodstream and brain infections which are life-threatening. The proposed studies will test whether and how activation of the liver prevents the spread of infection and disease from the lung to other organs. This new knowledge will guide further studies aiming to identify people who are especially susceptible and bacteria that are especially virulent, in order to better prevent and treat pneumococcal infections.